Essential information for architects, designers, engineers, equipment suppliers, and other professionals who are working in or entering the biopharmaceutical manufacturing field

Biomanufacturing facilities that are designed and built today are radically different than in the past. The vital information and knowledge needed to design and construct these increasingly sophisticated biopharmaceutical manufacturing facilities is difficult to find in published literatureand its rarely taught in architecture or design schools. This is the first book for architects and designers that fills this void.Process Architecture in Biomanufacturing Facility Design provides information on design principles of biopharmaceutical manufacturing facilities that support emerging innovative processes and technologies, use state-of-the-art equipment, are energy efficient and sustainable, and meet regulatory requirements.

Relying on their many years of hands-on design and operations experience, the authors emphasize concepts and practical approaches toward design, construction, and operation of biomanufacturing facilities, including product-process-facility relationships, closed systems and single use equipment, aseptic manufacturing considerations, design of biocontainment facility and process based laboratory, and sustainability considerations, as well as an outlook on the facility of the future.

Process Architecture in Biomanufacturing Facility Design is an ideal text for professionals involved in the design of facilities for manufacturing of biopharmaceuticals and vaccines, biotechnology, and life-science industry, including architects and designers of industrial facilities, construction, equipment vendors, and mechanical engineers. It is also recommended for university instructors, advanced undergraduates, and graduate students in architecture, industrial engineering, mechanical engineering, industrial design, and industrial interior design.

Jeffery Odum, CPIP is the Managing Partner of the Strategic Manufacturing Concept Group, and a Global Technology Partner at NNE in the US Office located in Durham, North Carolina and a Teaching Fellow in the BTEC program at North Carolina State University.

Michael C. Flickinger, PhD is the Associate Director for Academic Programs at the Golden LEAF Biomanufacturing Training and Education Center (BTEC) and a Professor of Chemical and Biomolecular Engineering at North Carolina State University, Raleigh, North Carolina.

Contributors xv

Foreword xvii

Preface xix

1 Introduction to Biomanufacturing1
Mark F. Witcher

1.1 Introduction 1

1.2 The Basics Constituents of Biopharmaceuticals 2

1.2.1 Proteins 3

1.2.2 Nucleic Acids (DNA and RNA) 5

1.2.3 Cells 6

1.3 Enterprise Element #1Manufacturing Processes 8

1.3.1 ProcessUnit Operations 8

1.3.2 Upstream ProcessesInoculum through Production Bioreactor 9

1.3.3 Upstream ProcessesHarvest and Recovery 12

1.3.3.1 Normal Filtration 12

1.3.3.2 Centrifuge 13

1.3.3.3 Cell Disruption 13

1.3.4 Downstream Processes 13

1.3.4.1 Viral Clearance 14

1.3.4.2 Tangential Flow Filtration 15

1.3.4.3 Chromatography 16

1.3.5 Process Performance and Control 19

1.3.6 ProcessEquipment 22

1.3.7 ProcessMaterials 23

1.4 Enterprise Element #2Manufacturing Facility 23

1.4.1 FacilityLayout 23

1.4.2 FacilityEnvironment 25

1.4.3 Clean Rooms/CNC Spaces 25

1.4.4 HVACHeating Ventilation and Air-Conditioning 26

1.4.5 Surfaces 30

1.4.6 FacilityUtilities Systems 30

1.4.7 FacilityControl Systems 31

1.5 Enterprise Element #3Manufacturing Infrastructure 31

1.5.1 InfrastructurePeople (Operating Staff) 32

1.5.2 InfrastructureEnterprise Practices and Procedures 32

1.6 Controlling the Manufacturing Enterprise 33

1.7 Summary 35

References 36

2 ProductProcessFacility Relationship39
Jeffery Odum

2.1 Introduction 39

2.2 The Characteristics of Biological Therapeutic Products 40

2.3 Understanding the Attributes 42

2.3.1 Product Quality Attributes 44

2.3.2 Process Parameters 44

2.3.3 Facility Attributes 45

2.4 Factors that Impact Facility Design 46

2.4.1 Facility Types 47

2.4.1.1 Product Development Facilities 47

2.4.1.2 Pilot/Clinical 49

2.4.1.3 Commercial Manufacturing 54

2.4.2 Comparisons of the Facility Types 54

References 54

3 Regulatory Considerations of Biomanufacturing Facilities55
Kip Priesmeyer

3.1 Introduction 55

3.2 Regulatory Uncertainty, A Two-Way Street 56

3.3 Design with the Patient in Mind: Assess the Patient, Product, Process, and Plant 58

3.4 Laws, Regulations, and Guidelines: Historical Background 60

3.5 Global Guidance Documents 64

3.6 Quality Systems and Risk Management 66

3.7 Product Changeover and Regulatory Assessment of Cleaning Validation 70

3.8 Control Strategy 74

3.9 Contract Manufacturing Organizations 77

3.10 FDA Inspections of Biopharm Facilities and Regulators Priorities 80

3.11 Regulatory Meetings 84

3.12 Conclusion 85

References 88

4 Biopharmaceutical Facility Design and Validation91
Jeffery Odum

4.1 Introduction 91

4.2 Designing for Compliance 92

4.2.1 Facility Considerations 93

4.2.2 ProductProcessFacility Integration 94

4.2.3 The Role of Quality by Design 94

4.3 Risk Management 102

4.4 Qualification/Verification 105

4.5 Process Validation 110

4.6 List of Abbreviations 113

References 115

5 Closed Systems in Bioprocessing117
Jeffery Odum

5.1 Introduction 117

5.2 Definition of Closed Systems 117

5.3 Closed System Design 119

5.4 Impact on Facility Design 121

5.5 Impact on Operations 123

5.6 Summary 127

References 127

6 Aseptic Manufacturing Considerations for Biomanufacturing Facility Design129
Jeffery Odum, Hartmut Schaz, and Larry Pressley

6.1 Introduction 129

6.2 The Relationship to Biological Products 130

6.3 Process AttributesProduct Protection 130

6.3.1 System Closure 131

6.3.2 Segregation Strategy 133

6.4 Facility Design 134

6.5 Critical Area 137

References 141

7 Facility Control of Microorganisms: Containment and Contamination143
Jonathan Crane

7.1 Introduction 143

7.2 Design Principles for Controlling Microorganisms 144

7.2.1 Planning Concepts 145

7.2.2 Physical Barriers 145

7.2.3 Engineering Systems 146

7.2.4 Containment and Isolation Equipment 150

7.2.5 Design to Support Operational Protocols 151

7.3 Controlling Viable Environmental Particulates 151

7.4 Reducing the Transport of Mold into the Bioprocess Facility 153

7.4.1 Environmental Zoning 153

7.4.2 Filtration of Molds and Mold Spores from Incoming Air 155

7.5 Reducing Mold Sources within the Bioprocess Facility 156

7.5.1 Cleaning and Decontamination 157

7.6 Biocontainment: An Overlay to Process Design 157

7.7 The Biocontainment Regulatory Environment 159

7.7.1 Laboratory-Scale Use and Use in Animal Models of Disease 160

7.7.2 Large-Scale Use of Pathogens 161

7.7.3 Animal and Plant Pathogens 162

7.7.4 Genetically Modified Organisms (GMO) and Synthesized Organisms 163

7.7.5 Toxins 163

7.7.6 Allergens and Biologically Active Products 164

7.7.7 Biosecurity 164

7.8 Principles of Biosafety 165

7.8.1 Risk Groups 165

7.8.2 Biosafety Levels 165

7.9 Principles of Biocontainment Facility Design 167

7.9.1 Risk Assessment 168

7.9.2 Primary Containment 168

7.9.3 Secondary Containment 169

7.9.4 Impact of Scale and Process 170

7.10 Design for the Entire Process 171

7.10.1 Upstream Process Facilities 172

7.10.2 Downstream Process Facilities 173

7.10.3 Fill and Finish Facilities 173

7.10.4 Quality Control Laboratory Facilities 173

7.10.5 Cross-contamination Live to Nonlive 173

7.11 Conclusion 173

References 174

Further Reading 176

8 Process-Based Laboratory Design177
Henriette Schubert and Flemming K. Nielsen

8.1 Introduction 177

8.2 Areas of Application/Scope 177

8.3 Translation of Process Elements into Laboratory Architecture 179

8.4 Key Steps in Planning Approach and Methodology 180

8.4.1 Laboratory Planning Process 180

8.4.1.1 Project Initiation (Analyze Data) 181

8.4.1.2 Conceptual Design (Develop Concepts) 181

8.4.1.3 Basic Design and Detailed Design (Develop Solutions) 181

8.4.2 Creating an Informed Basis for Design 182

8.4.2.1 Mapping of Design Drivers and Project Targets 183

8.4.2.2 Designing for the Desired Laboratory Work Culture 185

8.4.2.3 Risk Assessment (GMP, Biocontainment/High Potent Product Containment) 188

8.4.2.4 Operational Workflow Mapping and Visual Planning 193

8.4.2.5 Functional Adjacency Analysis (Function/Relation) 195

8.4.2.6 Laboratory Typologies as a Planning Tool 197

8.5 Laboratory Concept Development 200

8.5.1 Planning Considerations for Laboratory Concepts 200

8.5.1.1 Area Distribution 200

8.5.1.2 Laboratory Concepts 201

8.5.1.3 Capacity Considerations 201

8.5.1.4 Translating Strategic Project Drivers into Laboratory Concepts 202

8.5.1.5 Generic Versus Tailor-Made/Specialized Laboratory Concepts 203

8.5.1.6 Typical Objectives for Laboratory Types (R&D, QC) 204

8.5.1.7 Laboratory Planning Modules and Floor Height 206

8.5.2 Mechanical Considerations 208

8.6 SHE Considerations 209

8.7 Glossary 210

8.8 List of Abbreviations 210

References 211

9 Case Study: Pharmaceutical Pilot Plant Design and Operation213
Beth H. Junker

9.1 Introduction 213

9.2 Operational Concepts and Processing Requirements 215

9.3 Design 217

9.3.1 Process Equipment 219

9.3.2 Utilities 223

9.3.2.1 Product Contact 224

9.3.2.2 Nonproduct Contact 227

9.3.2.3 HVAC 228

9.3.3 Containment 230

9.3.3.1 Product Protection 231

9.3.3.2 Environmental Protection 231

9.3.3.3 Personnel Protection 232

9.3.4 Instrumentation 232

9.3.5 Automation and Control 233

9.3.6 Data Acquisition and Archiving 235

9.3.7 Warehousing 236

9.3.8 Back-Up Systems/Redundancy 237

9.3.9 Future Expansion/Modification 237

9.4 Operation 238

9.4.1 Maintenance 238

9.4.1.1 Preventative 238

9.4.1.2 Ongoing 240

9.4.1.3 Calibrations 240

9.4.1.4 Modifications/Change Control 241

9.4.2 Staffing 242

9.4.3 Laboratory Support 243

9.4.4 Standard Operating Procedures (SOPs) 243

9.4.5 Safety 247

9.4.6 Training 249

9.4.7 Validation 250

9.4.8 Facility Records and Manufacturing Execution Systems (MES) 251

References 253

10 Addressing Sustainability in Biomanufacturing Facility Design259
Josh Capparella, Samuel Colucci, Daniel Conner, Robert Dick, and Amanda Weko

10.1 Introduction 259

10.1.1 Economics of Sustainability 261

10.1.2 Energy Benchmarking in the Biopharmaceutical Industry 261

10.1.3 Integrating Sustainability into the Design Process 261

10.1.3.1 Building Sustainability into the Process Early 261

10.1.3.2 Building Information Modeling 262

10.1.3.3 Integrated Utilities Approach 262

10.1.4 Sustainable Building Benchmarking 263

10.1.4.1 Commercial Building Benchmarking 263

10.1.4.2 Biopharmaceutical Building Benchmarking 265

10.1.4.3 Variations in Benchmarking Data 266

10.1.4.4 Making a Meaningful Impact to Facility Energy Reductions 267

10.1.4.5 Energy Efficiency: Current Trends 268

10.1.5 Cost of Utilities 269

10.1.6 Is Net Zero a Possibility? 271

10.1.7 Process Drives the Design 272

10.1.8 Risk-Based Approach to Sustainability 272

10.1.9 Risk in a Closed Process 273

10.2 Process Architecture 273

10.2.1 Process Technology Impact on Footprint 273

10.2.2 Tech Transfer and Scale Up 274

10.2.3 Water 276

10.3 Water and Water Treatment 276

10.3.1 Incoming City Water 277

10.3.2 Filtration and Softening 277

10.3.3 Deionization and Reverse Osmosis 278

10.3.4 Water for Injection (WFI) 279

10.3.4.1 Ambient, Intermediate, and Hot WFI Requirements 279

10.3.5 Clean Steam 279

10.3.6 Black Utilities 280

10.3.7 Wastewater Treatment 280

10.4 Energy Efficiency 281

10.4.1 Building Envelope and Materials 281

10.4.2 Heating, Ventilation, and Air Conditioning (HVAC) 282

10.4.2.1 Once-Through HVAC Versus Recirculation 283

10.4.2.2 Filtration 283

10.4.2.3 PrimarySecondary Air 283

10.4.2.4 Setback Strategies 283

10.4.3 Chilled Water 285

10.4.3.1 Chilled Water and the HVAC System 286

10.4.3.2 Chilled Water Generation 286

10.4.3.3 Chilled Water Analysis and Design 286

10.4.3.4 Free Cooling Opportunities 288

10.4.3.5 Cooling Tower Design 289

10.4.4 Steam 289

10.4.4.1 Steam Optimization 289

10.4.5 Compressed Air 291

10.4.5.1 Air- and Water-Cooled Air Compressors 293

10.4.5.2 Drier Technology 293

10.4.6 Nitrogen 294

10.4.7 Retro Commissioning 294

10.4.8 Maintenance and Operations Best Practices 297

10.5 Conclusion 300

Acknowledgments 301

References 301

11 Technologys Impact on the Biomanufacturing Facility of the Future305
Jeffery Odum and Mark F. Witcher

11.1 Introduction 305

11.2 The Enabling Technologies 307

11.2.1 Process Platform Improvements 307

11.2.2 Single-Use Technology 308

11.2.3 Process Automation 311

11.3 Elements of a Biomanufacturing Enterprise 311

11.4 Evolution of the Facility of the Future 313

11.5 The FutureSummary and Conclusions 320

References 321

Glossary 323

Index 329